As used in the present specification the designation GLP-1 comprises GLP-1(7-37) as well as GLP-1(7-36)amide.
Glucose-induced insulin secretion is modulated by a number of hormones and neurotransmitters. In particular, two gut hormones, glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP) potentiate the effect of glucose on insulin secretion and are thus called gluco-incretins (Dupre, in The Endocrine Pancreas, E. Samois Ed. (Raven Press, New York, (1991), 253-281) and Ebert and Creutzfeld, (Diabetes Metab. Rev. 3, (1987)). Glucagon-like peptide-1 is a gluco-incretin both in rat and in man (Dupre and Ebert and Creutzfeld, vide supra, and Kreymann et al. (Lancet 2 (1987), 1300)). It is part of the preproglucagon molecule (Bell et al. Nature 304 (1983), 368) which is proteolytically processed in intestinal L cells to GLP-1(1-37) and GLP-1(7-36)amide or GLP-1(7-37) (Mojsov et al. (J.Biol.Chem. 261 (1986), 11880) and Habener et al.: The Endocrine Pancreas E. Samois Ed. (Raven Press, New York (1991), 53-71). Only the truncated forms of GLP-1 are biologically active and both have identical effects on insulin secretion in beta cells (Mojsov et al. J.Clin.Invest 79 (1987), 616) and Weir et al. (Diabetes 38 (1989), 338). They are the most potent gluco-incretins so far described and are active at concentrations as low as one to ten picomolar. The stimulatory effect of these gluco-incretin hormones requires the presence of glucose at or above the normal physiological concentration of about 5 mM and is mediated by activation of adenylate cyclase and a rise in the intracellular concentration of cyclic AMP (Drucker et al. Proc.Natl.Acad.Sci. USA 84 (1987), 3434) and Goke et al. (Am.J.Physiol. 257 (1989), G397). GLP-1 has also a stimulatory effect on insulin gene transcription (Drucker et al. Proc.Natl.Acad.Sci. USA 84 (1987), 3434). In a rat model of non-insulin-dependent diabetes mellitus (NIDDM), NIDDM is associated with a reduced stimulatory effect of GLP-1 on glucose-induced insulin secretion (Suzuki et al. Diabetes 39 (1990), 1320). In man, in one study, GLP-1 levels were elevated in NIDDM patients both in the basal state and after glucose ingestion; however, following a glucose load there was only a very small rise in plasma insulin concentration (.O slashed.rskov et al. J.Clin.Invest. 87 (1991), 415). A recent study (Nathan et al. Diabetes Care 15 (1992), 270) showed that GLP-1 infusion could ameliorate postprandial insulin secretion and glucose disposal in NIDDM patients. Thus, as a further step in understanding the complex modulation of insulin secretion by gut hormones and its dysfunction in diabetes, we isolated and characterized a complementary DNA for the beta cell GLP-1 receptor and showed that it is part of a new family of G-coupled receptors.